CN1575173A - Macrolides containing pharmaceutical compositions - Google Patents
Macrolides containing pharmaceutical compositions Download PDFInfo
- Publication number
- CN1575173A CN1575173A CNA028211588A CN02821158A CN1575173A CN 1575173 A CN1575173 A CN 1575173A CN A028211588 A CNA028211588 A CN A028211588A CN 02821158 A CN02821158 A CN 02821158A CN 1575173 A CN1575173 A CN 1575173A
- Authority
- CN
- China
- Prior art keywords
- chemical compound
- amino
- ammediol
- formula
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 22
- 239000003120 macrolide antibiotic agent Substances 0.000 title description 3
- 229940041033 macrolides Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 18
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 47
- 201000010099 disease Diseases 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- 238000012856 packing Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 2
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical compound OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 abstract 1
- 241001465754 Metazoa Species 0.000 description 16
- 150000003839 salts Chemical group 0.000 description 11
- 241000700159 Rattus Species 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 7
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000000902 placebo Substances 0.000 description 6
- 229940068196 placebo Drugs 0.000 description 6
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 6
- 201000004982 autoimmune uveitis Diseases 0.000 description 5
- -1 carrier Substances 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- 230000036039 immunity Effects 0.000 description 5
- BKMMTJMQCTUHRP-UHFFFAOYSA-N 2-aminopropan-1-ol Chemical compound CC(N)CO BKMMTJMQCTUHRP-UHFFFAOYSA-N 0.000 description 4
- 206010018364 Glomerulonephritis Diseases 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 230000002354 daily effect Effects 0.000 description 4
- 239000012453 solvate Chemical group 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010003645 Atopy Diseases 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 208000027496 Behcet disease Diseases 0.000 description 3
- 208000009137 Behcet syndrome Diseases 0.000 description 3
- 208000002691 Choroiditis Diseases 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 3
- 206010012438 Dermatitis atopic Diseases 0.000 description 3
- 206010012442 Dermatitis contact Diseases 0.000 description 3
- 208000004232 Enteritis Diseases 0.000 description 3
- 208000009329 Graft vs Host Disease Diseases 0.000 description 3
- 208000001204 Hashimoto Disease Diseases 0.000 description 3
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 3
- 208000003971 Posterior uveitis Diseases 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 208000021386 Sjogren Syndrome Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 description 3
- 206010047115 Vasculitis Diseases 0.000 description 3
- 239000002253 acid Chemical group 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000010247 contact dermatitis Diseases 0.000 description 3
- 208000024908 graft versus host disease Diseases 0.000 description 3
- 229960003444 immunosuppressant agent Drugs 0.000 description 3
- 230000001861 immunosuppressant effect Effects 0.000 description 3
- 239000003018 immunosuppressive agent Substances 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 229960002930 sirolimus Drugs 0.000 description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020565 Hyperaemia Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 108010081690 Pertussis Toxin Proteins 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000002159 anterior chamber Anatomy 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 2
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 125000003884 phenylalkyl group Chemical group 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- ZMKGDQSIRSGUDJ-VSROPUKISA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-30-propyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,1 Chemical compound CCC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-VSROPUKISA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 206010015943 Eye inflammation Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- ZMKGDQSIRSGUDJ-UHFFFAOYSA-N NVa2 cyclosporine Natural products CCCC1NC(=O)C(C(O)C(C)CC=CC)N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GDVNLLJNADMLLR-BBRMVZONSA-N Spergualin Chemical compound NCCCNCCCCNC(=O)[C@H](O)NC(=O)C[C@@H](O)CCCCN=C(N)N GDVNLLJNADMLLR-BBRMVZONSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 101710137302 Surface antigen S Proteins 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 108010019249 cyclosporin G Proteins 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 210000001699 lower leg Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229950000844 mizoribine Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940014456 mycophenolate Drugs 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000001982 uveitic effect Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Hematology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Neurosurgery (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Transplantation (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Neurology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Disclosed is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable 2-amino-1,3-propanediol beside one or more pharmaceutically acceptable excipient(s).
Description
The present invention relates to pharmaceutical composition, for example be used for the treatment of pathological condition, comprise co-administered activating agent with pharmaceutically active.Treatment comprises and preventing and/or treating.
On the one hand, the invention provides the pharmaceutical active compounds of formula I,
As the disclosed chemical compound of EP427680 (the 33-table-33-chloro-FR520 among the embodiment 66a) and 2-amino-1, ammediol and one or more pharmaceutically useful excipient.
One or more pharmaceutically useful excipient for example comprise one or more pharmaceutically useful auxiliary agents, carrier, diluent.2-amino-1, ammediol can comprise one or more 2-amino-1, ammediol.
Known formula I chemical compound has activity for the various condition/disease of treatment, as for example inflammatory situation, immune-mediated disease, or autoimmune disease, vasculitis for example, glomerulonephritis (glomerulonephritides), atopic dermatitis, irritated (atopy contact eczema for example, asthma), psoriasis, systemic lupus erythematosus (sle), rheumatoid arthritis, inflammatory bowel (segmental enteritis for example, ulcerative colitis), multiple sclerosis, insulin dependent diabetes mellitus (IDDM), sjogren syndrome, endogenous posterior uveitis (uveitide) (especially behcet disease), chronic lymphocytic thyroiditis, and prevention xenograft or allograft, for example comprise heart, kidney, the repulsion that liver or bone marrow graft cause; Grafting vessel disease or graft versus host disease.
The 2-amino of herein mentioning-1, ammediol comprise formula II chemical compound,
Wherein:
R
1Be the optional straight or branched (C that replaces
12-22) carbochain, alkyl chain for example, it is optional be substituted or unsubstituted phenylene at interval, and R
2, R
3, R
4And R
5Be H or low alkyl group independently of one another.Work as R
1When the carbochain of indication was substituted, it was preferably by halogen, nitro, amino, hydroxyl or carboxyl substituted.The phenyl that is optionally substituted when carbochain is at interval the time, and carbochain is preferably unsubstituted.When phenylen moiety was substituted, it was preferably by halogen, nitro, amino, methoxyl group, hydroxyl or carboxyl substituted." low alkyl group " comprises (C
1-4) alkyl.These chemical compounds for example are disclosed among EP627406, EP778263, EP1002792 or the WO02/06268, and the content of its related content, especially relevant described chemical compound is hereby incorporated by.
Preferred chemical compound comprises formula II chemical compound, wherein R
1(C for straight or branched, preferred straight chain
13-20) carbochain, optional by nitro, halogen, amino, hydroxyl or carboxyl substituted, and more preferably formula II chemical compound, wherein R
1Be the optional phenylalkyl that is replaced by halogen, for example wherein alkyl is the optional (C that is replaced by hydroxyl
1-6) alkyl, and wherein phenyl by straight or branched (C
6-14) alkyl replaces and optionally replaced by halogen.More preferably, R
1Be phenyl (C
1-6) alkyl, phenyl wherein is by straight or branched, preferred straight chain (C
6-14) the alkyl replacement, as (C
6-14) alkyl-phenyl-(C
1-6) alkyl.If R
1Be phenylalkyl, phenyl wherein is by straight or branched (C
6-14) alkyl replaces, then phenyl can by alkyl at the ortho position, a position or para-position, preferably at para-orientation.Preferred R
2To R
5Each be H.
Pharmaceutical composition can comprise formula I chemical compound and 2-amino-propanol, for example a kind of 2-amino-propanol described in the EP778263, and one or more pharmaceutically useful excipient.
In a further preferred embodiment, 2-amino-1, ammediol or 2-amino-propanol are the chemical compound with lymphocyte homing character.This character can according to as for example following test differentiate: with test compound or excipient by raising by oral administration to rat by force.Got tail blood in 2,6,24,48 and 72 hours and be used for hematology's monitoring using the back, got tail blood to provide the baseline individual value in the 11st day.The lymphocyte homing agent is a kind of like this chemical compound: for example using less than 5mg/kg, preferably behind the dosage less than 3mg/kg, peripheral blood lymphocytes was being reduced in its 6 hours and surpass 50%.
Still preferred formula II chemical compound is a formula IIa chemical compound,
2-amino-2[2-(4-octyl phenyl) ethyl for example] propane-1, the 3-diol hydrochloride.Based on observed activity, for example described in the EP627406,2-amino-1, ammediol for example formula II chemical compound can be used as immunomodulator, for example for example immunosuppressant in the treatment allograft rejection.For example as described in the WO98/22100, the 2-amino-1 of formula II for example, ammediol can suppress the grafting vessel disease and be specially adapted to prevent or treat the chronic rejection of transplant organ, can suppress xenograft in addition and repel.
According to the present invention, 2-amino-1, ammediol or 2-amino-propanol have pharmaceutically active and are that pharmacy is acceptable.
As long as there is described form, formula I chemical compound and 2-amino-1, ammediol comprises any type of chemical compound, for example free form, salt form, solvate forms and salt and solvate forms.The The compounds of this invention of free form can change into the chemical compound of corresponding salt form; The free form of solvate forms or the The compounds of this invention of salt form can be converted into the free form of corresponding non-solvent compound form or the chemical compound of salt form, and vice versa.
The activity of the pharmaceutically active of the chemical compound of free form and the chemical compound of salt/solvate forms is in similar scope.Solvate comprises hydrate.Salt comprises pharmaceutically useful salt.
For example the officinal salt of formula II chemical compound comprises the salt that formula II chemical compound and acid form, described acid for example comprises mineral acid, example hydrochloric acid, hydrobromic acid and sulphuric acid, and comprise organic acid, as acetic acid, fumaric acid, maleic acid, benzoic acid, citric acid, malic acid, methanesulfonic acid and benzenesulfonic acid, if and had carboxyl, would also comprise the salt that forms with following material:
-metal such as sodium, potassium, calcium and aluminum,
-amine such as triethylamine and
-dibasic aminoacid such as lysine.
In a preferred embodiment, formula II chemical compound or the described chemical compound of those EP1002792 comprise the phosphate of described chemical compound.
Formula I chemical compound and formula II chemical compound can exist with isomeric form, and the present invention includes formula I chemical compound of the present invention and 2-amino-1, ammediol and any heterogeneous mixture of any isomeric form.If formula I chemical compound for example of the present invention and 2-amino-1, ammediol has one or more asymmetric centers in molecule, then the present invention includes the chemical compound of various optical isomer forms, and racemic modification, diastereomer and its mixture.
We now surprisingly find: formula I chemical compound or 2-amino-1 therein, ammediol can show in the animal model of experimental autoimmune uveitis (EVU) of pharmaceutically active, when with co-administered formula I chemical compound of for example suboptimum dosage and 2-amino-1, ammediol for example during formula II chemical compound, has obtained enhanced activity.The enhanced activity of co-administered chemical compound is significantly higher than the activity of every kind of unification compound being tested under suboptimum dosage level for example.It is believed that identical rule also is applicable to its Chinese style I chemical compound or 2-amino-1, ammediol shows all diseases of pharmaceutically active, for example comprise the inflammatory situation, immune-mediated disease, or autoimmune disease, vasculitis for example, glomerulonephritis, atopic dermatitis, irritated (atopy contact eczema for example, asthma), psoriasis, systemic lupus erythematosus (sle), rheumatoid arthritis, inflammatory bowel (segmental enteritis for example, ulcerative colitis), multiple sclerosis, insulin dependent diabetes mellitus (IDDM), sjogren syndrome, endogenous posterior uveitis (especially behcet disease), chronic lymphocytic thyroiditis, and prevent xenograft or allograft for example to comprise heart, kidney, the repulsion that liver or bone marrow graft cause; Grafting vessel disease or graft versus host disease.
On the other hand, the invention provides a kind of packing, it comprises the pharmaceutical composition of formula I chemical compound and one or more pharmaceutically acceptable excipient, and comprises and be used for simultaneously or use 2-amino-1, the description of ammediol successively.
On the other hand, the invention provides a kind of packing, it comprises 2-amino-1, the pharmaceutical composition of ammediol and one or more pharmaceutically acceptable excipient, and comprise the description that is used for simultaneously or uses formula I chemical compound successively.
On the other hand, the invention provides pharmaceutical pack, for example a kind of packing, it comprises the pharmaceutical composition of formula I chemical compound and one or more pharmaceutically acceptable excipient in same packing, and 2-amino-1, the pharmaceutical composition of ammediol and one or more pharmaceutically acceptable excipient.
On the other hand, the invention provides the method for the pharmaceutically active that improves foregoing formula I chemical compound, this method comprises to needs formula I chemical compound and/or 2-amino-1, the co-administered formula I chemical compound of object and the 2-amino-1 of ammediol treatment, ammediol.
Formula I chemical compound and 2-amino-1, ammediol can be co-administered in a different manner:
A), comprise the formula I chemical compound and the 2-amino-1 with pharmaceutically active, ammediol that are in the same pharmaceutical composition with the form of fixed combination;
B) with the form of (medicine) bag, its Chinese style I chemical compound and 2-amino-1, ammediol exists with the separated drug composition forms, for example be used for co-administered description and sell in same packing.
C) with the form of independent assortment, its Chinese style I chemical compound and 2-amino-1, ammediol is for example packed respectively with the form of pharmaceutical composition, and wherein each packing includes and is used for simultaneously or the description of using successively.
Formula I chemical compound and 2-amino-1, the most effective ratio of ammediol can be depending on indication for example to be treated.Appropriate dosage and dosage range will change according to for example employed reactive compound of the present invention, host, method of application and the sanatory character of institute and seriousness certainly.But, generally speaking, in order for example to realize satisfactory results in the human body bigger mammal, the daily dose that is suitable for is the formula I chemical compound of macrolide such as pharmaceutically active and the 2-amino-1 of pharmaceutically active, the known dose of ammediol, for example be lower than these optimal doses, for example use to be no more than divided dose, for example every day 4 times.Usually, obtain the satisfied needed daily dose of result at whole body and be the formula I chemical compound of about 0.5mg/kg to about 15mg/kg, preferred 1mg/kg to about 15mg/kg animal/body weight for humans and the formula II chemical compound of about 0.005mg/kg to 0.1mg/kg, preferred 0.01mg/kg to 0.1mg/kg.The ratio of preferred Compound I and II is about 3000 to 10, preferred 500 to 10.
Reactive compound of the present invention can be used by the approach of any routine, and is for example by whole body, for example oral, for example uses with tablet or capsular form; Or, for example use with the form of injection solution or suspension by parenteral; And use in local application such as epidermis, intranasal, the trachea.
On the other hand, the invention provides treatment its Chinese style I chemical compound and/or 2-amino-1, ammediol has the method for the disease of pharmaceutically active, described disease for example comprises the inflammatory situation, immune-mediated disease or autoimmune disease, vasculitis for example, glomerulonephritis, atopic dermatitis, irritated (atopy contact eczema for example, asthma), psoriasis, systemic lupus erythematosus (sle), rheumatoid arthritis, inflammatory bowel (segmental enteritis for example, ulcerative colitis), multiple sclerosis, insulin dependent diabetes mellitus (IDDM), sjogren syndrome, endogenous posterior uveitis (especially behcet disease) or chronic lymphocytic thyroiditis, and prevent xenograft or allograft for example to comprise heart, kidney, the repulsion that liver or bone marrow graft cause; Grafting vessel disease or graft versus host disease, described method comprise formula I chemical compound from effective dose to the object of this treatment of needs and the 2-amino-1 of using, and ammediol is for example used with following form:
-fixed combination, for example form of pharmaceutical composition;
-(medicine) wraps, and for example is in the pharmaceutical composition and the 2-amino-1 of the formula I chemical compound in the same packing, the form of the pharmaceutical composition of ammediol;
-a kind of packing comprises for example the formula I chemical compound or the 2-amino-1 of pharmaceutical compositions, ammediol, and comprise and be used for simultaneously or co-administered successively description.
In a preferred embodiment of the invention, formula I chemical compound and formula IIa chemical compound are co-administered.
Formula I chemical compound and 2-amino-1, ammediol can be used as unique composition or the other medicines in the immunomodulating scheme or other antiinflammatory and use.For example described chemical compound can use with following drug regimen: cyclosporin, rapamycin or other ascosin, or their immunosuppressant analog, for example cyclosporin A, cyclosporin G, FK-506, rapamycin, 40-O-(2-hydroxyl) ethyl-rapamycin etc.; Corticosteroid; Cyclophosphamide; Azathioprine; Methotrexate; Bai Ruikuaer; Take fluorine Lip river rice; Mizoribine; Mycophenolic acid; Mycophenolate; 15-deoxidation Antibiotic BMG-162aF2; The immunosuppressant monoclonal antibody is for example at leukocyte receptors for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45 or CD58 or at their monoclonal antibody of part; Or other immunomodulatory compounds CTLA4-1g for example.
Be used to measure formula I chemical compound and 2-amino-1, the active test method(s) of ammediol is known.Can use for example Clin.Immunol.Immunopathol.1986,39:329-336, the described experimental autoimmune uveitis of people such as McAllister (EAU) model.
On the other hand, for example the invention provides simultaneously or formula I chemical compound and the 2-amino-1 used successively, ammediol is as the purposes of medicine; And formula I chemical compound and 2-amino-1, the preparation that is combined in of ammediol is used for the treatment of purposes in the medicine of disease, described disease Chinese style I chemical compound or 2-amino-1, and ammediol has pharmaceutically active.Treatment comprises and preventing and/or treating.
Brief description
Fig. 1 is presented at the result of experimental autoimmune uveitis (EAU) test of carrying out in the rat.
With following material oral medication rat once a day, 14 days by a definite date,
-◆-: contrast (placebo, i.e. drug excipient/water),
-■-: formula IIa chemical compound (0.1mg),
-▲-: formula I chemical compound (15mg), or
Formula IIa chemical compound (0.1mg)+formula I chemical compound (15mg).
Weight in mg is expressed as the mg/kg body weight/day.The scoring average of eyes infringements is measured as described in embodiment in back 20 days in immunity.
Fig. 2 is presented at the result of experimental autoimmune uveitis (EAU) test of carrying out in the rat.
With following material oral medication rat once a day, 14 days by a definite date,
-◆-: contrast (placebo, i.e. drug excipient/water),
-■-: formula IIa chemical compound (0.1mg),
-▲-: formula I chemical compound (15mg),
Formula I chemical compound (15mg)+formula IIa chemical compound (0.1mg), 14 days, or
-*-: formula I chemical compound (15mg)+formula IIa chemical compound (0.1mg), 28 days.
Other parameter as described in Figure 1.
Embodiment
Embodiment 1:EAU pilot system
Experimental autoimmune uveitis (EAU)
Employed EAU model class is similar to the previous described model of people such as McAllister (1986) (McAllister CG, Vistica BP, Sekura R, Kuwabara T, Gery l. " pertussis toxin, PT is to the uveitic effect of inducing and shifting of experimental autoimmune " Clin ImmunolImmunopathol 1986; 39:329-336).Under etherization, injected the bovine retina S-antigen of 50 μ g purification and through peritoneal injection 1 μ g pertussis toxin, PT (Difco) at first day to the right crus of diaphragm pad of animal (every group of 5 rats).Antigen mixes with Freund's complete adjuvant and Bacto M pulmonary tuberculosis H37 RA (Difco) with the saline dilution of phosphate-buffered and with 1: 1 ratio.Volume injected is 0.1ml, contains 50 μ l Freund's complete adjuvants and 1.14mg Mycobacterium tuberculosis.This operates in and all brings out burst (fulimant) disease in all animals, and it can be after immunity observes in initial 9 to 10 days.The eyes infringement of not treating animal all is developed to fractionated the 4th grade of seriousness (seeing " EAU evaluation " part) in nearly all animal.
Treatment, dosage
With gavage animal is treated, using daily dose is independent 15mg/kg formula I chemical compound or the formula IIa chemical compound of 0.1mg/kg, or uses two kinds of combination of compounds of same dose level.Treatment began in immunity in preceding 2 hours, and carried out once continuous 14 day every day.Control animal is with independent placebo/water (placebo: independent drug excipient) treat similarly.
EAU estimates
Beginning in the 7th day after immunity is with the inflammatory activity of ophthalmoscope (Heine, Beta 200) daily check animal, until the 20th day.The degree of eye inflammation is carried out semi-quantitative assessment with 0 to 4 classification (for eyes):
0: normal;
1: iris hyperemia;
2: iris hyperemia, comes expansion;
3: have early stage fibrin exudate and moderate iris cells to soak into the anterior chamber; With
4: have large-area fibre albumen grumeleuse or fibrin to stop up pupil and serious iris cells infiltration the anterior chamber.
The result
There are not significantly different (referring to for example table 1 and Fig. 1) aspect the process of disease and the intensity with the placebo group with the animal (LEWIS rat) of the formula I chemical compound oral administration treatment of the formula IIa chemical compound of 0.1mg/kg or 15mg/kg/ days.
In contrast, use two kinds of chemical compounds and make intensity that the outbreak of disease significantly postpones (than 6 days matched group evenings) and inflammation significantly with the same dose level a little less than.At the 19th day, the highest average score of treatment animal was 4.4, and the 11st day scoring of matched group is 8.0 by contrast.
Table 1
Test group | Dosage | ??EAU ??POS | ????EAU10 | ??EAU1 st | ??????SCORE?MAX | |
Scoring | My god | |||||
Contrast | ??0.0 | ??5/5 | ????5/5 | ??10.0(0.0) | ??8.0(0.0) | ??11 |
????Cpd?IIa | ??0.1 | ??4/4 *) | ????2/5 | ??10.5(0.6) | ??8.0(0.0) | ??13 |
????Cpd?I | ??15 | ??5/5 | ????1/5 | ??11.8(1.3) | ??6.8(1.3) | ??14 |
????Cpd?IIa+Cpd?I | ??1.5+15 | ??4/5 | ????0/5 | ??16(1.4) | ??4.4(3.3) | ??19 |
*)Experimental animal at the 11st day owing to wound due to raising by force comes off.
Under " the EAU POS " and " EAU10 " of table 1 item, shown every group of infected animal number/number of animals when research finishes (EAU POS) and the 10th day (EAU10) respectively.Used following abbreviation:
Cpd I: formula I chemical compound
Cpd IIa: formula IIa chemical compound
Contrast: placebo (drug excipient/water)
Dosage: oral, in mg/kg/ days
The positive number of rats of EAU POS:EAU
EAU10: the sickness rate of the 10th day EAU
EAU1
St: the date (mean value SD) of first EAU symptom
SCORE MAX: the highest scoring (the mean value SD of eyes infringement)
The result of EAU-test (as EXPERIMENTAL EXAMPLE) shows: the formula I chemical compound of suboptimum dosage and the formula IIa combination of compounds of suboptimum dosage significantly are being better than using separately respectively the formula I chemical compound of suboptimum dosage or the formula IIa chemical compound (table 1 and Fig. 1) of suboptimum dosage aspect the anti-EAU activity.This effect has approved that the formula I chemical compound of suboptimum dosage adds the use of the formula IIa chemical compound of suboptimum dosage.
Embodiment 2:
As the dosage treatment animal (every group of 6 rats) that provides as described in the embodiment 1, with table 2.As table 2 and shown in Figure 2, therapeutic alliance demonstrates the result who is better than with single compounds for treating.In the 14th day animal, in an animal, observed first clinical symptoms at the 16th day with two kinds of compounds for treating.Also observing symptom during the treatment in 4 weeks is suppressed fully.Symptom is early than the 34th day, and promptly last is treated and come across in the animal in back 6 days.
Table 2
Test group | Dosage | ??EAU?POS | ???EAU ???10 | ????EAU1 st | ?????????SCORE?MAX | |
Scoring | My god | |||||
Matched group | ????- | ??6/6 | ???6/6 | ????9.3(0.5) | ??8.0(0.0) | ??12 |
???Cpd?IIa | ????0.1 | ??6/6 | ???0/6 | ????11.2(1.0) | ??8.0(0.0) | ??14 |
???Cpd?I | ????15 | ??6/6 | ???2/6 | ????11.5(0.8) | ??6.0(2.5) | ??14 |
???Cpd?I+Cpd?IIa | ????15+0.1(14x) | ??6/6 | ???0/6 | ????18.0(1.1) | ??8.0(0.0) | ??21 |
???Cpd?I+Cpd?IIa | ????15+0.1(28x) | ??6/6 | ???0/6 | ????34.8(0.4) | ??7.2(1.3) | ??37 |
Implication is with the explanation of table 1.
The result of EAU test (as EXPERIMENTAL EXAMPLE) shows: when when immunity begins, carrying out 4 weeks treatments with the combination of Compound I and IIa, and the generation that can ward off disease.
Claims (10)
1. pharmaceutical composition, it comprises formula I chemical compound,
With 2-amino-1, ammediol, and one or more pharmaceutically useful excipient.
2. packing, it comprises the pharmaceutical composition of the defined formula I chemical compound of claim 1 and one or more pharmaceutically acceptable excipient, and comprises and be used for simultaneously or use 2-amino-1, the description of ammediol successively.
3. packing, it comprises 2-amino-1, the pharmaceutical composition of ammediol and one or more pharmaceutically acceptable excipient, and comprise the description that is used for simultaneously or uses the defined formula I chemical compound of claim 1 successively.
4. pharmaceutical pack, it comprises the pharmaceutical composition and the 2-amino-1 of the defined formula I chemical compound of the claim 1 that is in the same packing and one or more pharmaceutically acceptable excipient, the pharmaceutical composition of ammediol and one or more pharmaceutically acceptable excipient.
The defined formula I chemical compound of claim 1 with have the 2-amino-1 of pharmaceutically active, the combination of ammediol is as the purposes of medicine.
6. defined formula I chemical compound of claim 1 and 2-amino-1, the preparation that is combined in of ammediol is used for the treatment of purposes in the medicine of disease, described disease Chinese style I chemical compound and 2-amino-1, ammediol has pharmaceutically active.
7. improve formula I chemical compound and pharmaceutically useful 2-amino-1, the method for the pharmaceutically active of ammediol, this method comprise to needs formula I chemical compound and/or 2-amino-1, the co-administered formula I chemical compound of object and the 2-amino-1 of ammediol treatment, ammediol.
8. treat wherein defined formula I chemical compound of claim 1 and 2-amino-1, the method of the disease of ammediol tool pharmaceutically active, it comprises defined formula I chemical compound of claim 1 from effective dose to the object of this treatment of needs and the 2-amino-1 of using, ammediol.
9. each described method of aforementioned claim, pharmaceutical composition, pharmaceutical pack, packing or purposes, 2-amino-1 wherein, ammediol are formula II chemical compound,
R wherein
1Be the optional straight or branched (C that replaces
12-22) carbochain, and R
2, R
3, R
4And R
5Be H or low alkyl group independently of one another.
10. the described method of claim 9, pharmaceutical composition, pharmaceutical pack, packing or purposes, its Chinese style II chemical compound has following general formula:
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0125443.2 | 2001-10-23 | ||
GBGB0125443.2A GB0125443D0 (en) | 2001-10-23 | 2001-10-23 | Organic Compounds |
GB0127341A GB0127341D0 (en) | 2001-11-14 | 2001-11-14 | Organic compounds |
GB0127341.6 | 2001-11-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1575173A true CN1575173A (en) | 2005-02-02 |
CN1307993C CN1307993C (en) | 2007-04-04 |
Family
ID=26246689
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB028211588A Expired - Fee Related CN1307993C (en) | 2001-10-23 | 2002-10-22 | Macrolides containing pharmaceutical compositions |
Country Status (19)
Country | Link |
---|---|
US (1) | US7259170B2 (en) |
EP (1) | EP1439838A1 (en) |
JP (1) | JP2005509634A (en) |
KR (2) | KR20090114483A (en) |
CN (1) | CN1307993C (en) |
AU (1) | AU2002346859C1 (en) |
BR (1) | BR0213463A (en) |
CA (1) | CA2458690C (en) |
EC (1) | ECSP045086A (en) |
GB (1) | GB0125443D0 (en) |
HU (1) | HUP0402108A3 (en) |
IL (1) | IL160973A0 (en) |
MX (1) | MXPA04003738A (en) |
NO (1) | NO20042074L (en) |
NZ (1) | NZ532412A (en) |
PL (1) | PL368533A1 (en) |
RU (1) | RU2321402C2 (en) |
WO (1) | WO2003035068A1 (en) |
ZA (1) | ZA200401711B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002089796A2 (en) * | 2001-05-09 | 2002-11-14 | Novartis Ag | Methods for selective immunomodulation using pimecrolimus |
KR100836547B1 (en) | 2002-01-11 | 2008-06-10 | 상꾜 가부시키가이샤 | Amino alcohol derivative or phosphonic acid derivative and medicinal composition containing these |
GB0307867D0 (en) * | 2003-04-04 | 2003-05-14 | Novartis Ag | Pharmaceutical composition |
BRPI0507944A (en) | 2004-02-24 | 2007-07-24 | Sankyo Co | pharmaceutical composition |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE68921934T2 (en) | 1988-06-29 | 1995-10-19 | Merck & Co Inc | Immunosuppressive agent. |
US5352671A (en) * | 1989-11-09 | 1994-10-04 | Sandoz Ltd. | Heteroatoms-containing tricyclic compounds |
ATE126803T1 (en) * | 1989-11-09 | 1995-09-15 | Sandoz Ag | TRICYCLIC COMPOUNDS CONTAINING HETEROATOMS. |
GB2252041A (en) * | 1991-01-23 | 1992-07-29 | Fujisawa Pharmaceutical Co | Use of macrolide compounds in treatment of autoimmune myocarditis |
JPH06509559A (en) * | 1991-03-19 | 1994-10-27 | セラピューティック パッチ リサーチ エヌ.ブイ. | Amino alcohol derivative compositions and methods as membrane permeation enhancers |
GB9203636D0 (en) * | 1992-02-19 | 1992-04-08 | Lucas Ind Plc | Fuel pumping apparatus |
KR0155015B1 (en) | 1992-10-21 | 1998-12-01 | 고우야 마사시 | 2-amino-1,3-propanediol compound and immunosuppressant |
EP0689545A4 (en) | 1993-03-17 | 1996-04-24 | Abbott Lab | Macrocyclic amide and urea immunomodulators |
US5590460A (en) * | 1994-07-19 | 1997-01-07 | Tessera, Inc. | Method of making multilayer circuit |
ES2171191T3 (en) * | 1994-08-22 | 2002-09-01 | Mitsubishi Pharma Corp | COMPOSITE OF BENZENE AND MEDICINAL USE OF THE SAME. |
GB9521322D0 (en) | 1995-10-17 | 1995-12-20 | Sandoz Ltd | Organic compounds |
JPH11209277A (en) | 1998-01-19 | 1999-08-03 | Yoshitomi Pharmaceut Ind Ltd | Pharmaceutical composition |
GB9624038D0 (en) | 1996-11-19 | 1997-01-08 | Sandoz Ltd | Organic compounds |
DE69825056T2 (en) * | 1997-04-04 | 2005-08-25 | Mitsubishi Pharma Corp. | 2-AMINOPROPAN-1,3-DIOL COMPOUNDS, THEIR MEDICAL APPLICATION AND INTERMEDIATES TO THEIR SYNTHESIS |
GB9713730D0 (en) * | 1997-06-30 | 1997-09-03 | Ciba Geigy Ag | Organic compounds |
JP4627356B2 (en) * | 1999-06-30 | 2011-02-09 | 松森 昭 | Drugs for preventing or treating viral myocarditis |
GB0003932D0 (en) | 2000-02-18 | 2000-04-12 | Novartis Ag | Pharmaceutical compositions |
AU2002249826A1 (en) | 2000-12-22 | 2002-07-30 | Avantec Vascular Corporation | Delivery of therapeutic capable agents |
-
2001
- 2001-10-23 GB GBGB0125443.2A patent/GB0125443D0/en not_active Ceased
-
2002
- 2002-10-22 EP EP02782975A patent/EP1439838A1/en not_active Withdrawn
- 2002-10-22 AU AU2002346859A patent/AU2002346859C1/en not_active Ceased
- 2002-10-22 BR BR0213463-2A patent/BR0213463A/en not_active IP Right Cessation
- 2002-10-22 US US10/492,439 patent/US7259170B2/en not_active Expired - Fee Related
- 2002-10-22 MX MXPA04003738A patent/MXPA04003738A/en active IP Right Grant
- 2002-10-22 IL IL16097302A patent/IL160973A0/en unknown
- 2002-10-22 CA CA2458690A patent/CA2458690C/en not_active Expired - Fee Related
- 2002-10-22 PL PL02368533A patent/PL368533A1/en not_active Application Discontinuation
- 2002-10-22 KR KR1020097021354A patent/KR20090114483A/en not_active Application Discontinuation
- 2002-10-22 NZ NZ532412A patent/NZ532412A/en unknown
- 2002-10-22 WO PCT/EP2002/011799 patent/WO2003035068A1/en active Application Filing
- 2002-10-22 CN CNB028211588A patent/CN1307993C/en not_active Expired - Fee Related
- 2002-10-22 KR KR1020047005958A patent/KR100978971B1/en not_active IP Right Cessation
- 2002-10-22 JP JP2003537635A patent/JP2005509634A/en active Pending
- 2002-10-22 HU HU0402108A patent/HUP0402108A3/en unknown
- 2002-10-22 RU RU2004116067/15A patent/RU2321402C2/en not_active IP Right Cessation
-
2004
- 2004-03-02 ZA ZA200401711A patent/ZA200401711B/en unknown
- 2004-04-23 EC EC2004005086A patent/ECSP045086A/en unknown
- 2004-05-19 NO NO20042074A patent/NO20042074L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
KR100978971B1 (en) | 2010-08-30 |
NZ532412A (en) | 2006-01-27 |
AU2002346859B2 (en) | 2006-03-02 |
ECSP045086A (en) | 2004-06-28 |
GB0125443D0 (en) | 2001-12-12 |
US20040192716A1 (en) | 2004-09-30 |
HUP0402108A2 (en) | 2005-02-28 |
KR20040052250A (en) | 2004-06-22 |
NO20042074L (en) | 2004-05-19 |
RU2321402C2 (en) | 2008-04-10 |
CN1307993C (en) | 2007-04-04 |
IL160973A0 (en) | 2004-08-31 |
US7259170B2 (en) | 2007-08-21 |
MXPA04003738A (en) | 2004-07-23 |
RU2004116067A (en) | 2005-04-20 |
HUP0402108A3 (en) | 2008-02-28 |
AU2002346859C1 (en) | 2008-07-10 |
CA2458690C (en) | 2011-01-25 |
JP2005509634A (en) | 2005-04-14 |
BR0213463A (en) | 2004-11-09 |
WO2003035068A1 (en) | 2003-05-01 |
ZA200401711B (en) | 2004-10-21 |
PL368533A1 (en) | 2005-04-04 |
CA2458690A1 (en) | 2003-05-01 |
KR20090114483A (en) | 2009-11-03 |
EP1439838A1 (en) | 2004-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1084618C (en) | Use of serotonin antagonists (5HT3) for treating fibromyalgia | |
CN1145619C (en) | 1-4-benzothiazepine-1,1-dioxide derivatives substituted by sugar radicals, methods for the production thereof, medicaments containing these compounds and the use thereof | |
RU2396982C2 (en) | Effective method of using drugs and method for prevention of by-effects intensity | |
CN1213965A (en) | Use of antiarrhythmic compounds for reducing post-infarction morality | |
CN1043610C (en) | Novel treatment | |
KR101476591B1 (en) | Treatment of autoimmune diseases | |
CN1152304A (en) | Substituted benzamidines, their production and their use as medicaments | |
CN1522147A (en) | Composition for treating drug-induced constipation with 15-keto-prostaglandins | |
CN1292694A (en) | New use | |
CN1307993C (en) | Macrolides containing pharmaceutical compositions | |
CN1170536C (en) | Method for preventing vomit and sexual disorder using tetrahydrobenzo [cd] indole-6-formylamine compound | |
CN1340044A (en) | Nervinolin derivatives | |
CN1684681A (en) | Bicifadine formulation | |
CN1492757A (en) | Use of accelerated lymphocyte homing agents for manufacture of medicament for treating delayed graft function in tissue transplant | |
CN1053441C (en) | Compound with 1-(aryl Chain olefine)-4-(aryl methyl) piperazine structure, preparation process thereof and medicine thereof | |
CN1418630A (en) | Solution agent of antiallergi medicine contg. levocetirizine | |
CN1468601A (en) | Picroside-II as one new medicine for preventing and treating allergic and inflammatory diseases | |
CN1108095A (en) | Composition for prophylaxis and treatment of myopia | |
CN1759887A (en) | Mucous membrane absorption ingestion type medicinal composition for drawing out interferon, and preparation | |
CN1708308A (en) | Use of fosinopril to reduce cardiovascular events in dialysis patients | |
AU2002346859A1 (en) | Macrolides containing pharmaceutical compositions | |
CN1327386A (en) | Anti-HIV infection agents and method for treating HIV infection | |
CN1524518A (en) | Use of 2-amino-2(2-(4-octyl phenyl)ethyl)-1,3-propylene glycol in the preparation of medicaments of preventing and curing immune liver injury | |
CN1579389A (en) | Compound preparation for treating hypertension | |
CN87107599A (en) | 4-hydroxyl-4-(substituted alkenyl base) hexahydrobenzoic acid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070404 Termination date: 20131022 |